Pharmaceutical compositions comprising a MENIN inhibitor

Abstract

Described herein are crystalline forms of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof, methods of making such forms, and pharmaceutical composition comprising such forms.

We claim: 
     
         1 . A pharmaceutical composition comprising wet-milled crystalline of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof having a bulk density of at least 0.1 g/cm 3 . 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline form of (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an X-ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having a differential scanning calorimetry (DSC) thermogram with an endotherm having an onset at about 136° C. and/or a peak at about 149° C. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is obtained from methyl ethyl ketone (MEK) and isopropanol (IPA). 
     
     
         6 . The pharmaceutical composition of  claim 5 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is obtained from a 1:1 mixture of MEK and IPA. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof has a bulk density from about 0.1 to about 0.15 g/cm 3 . 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof has a particle size distribution of D 10 , 1.5 to 4.5 μm; D 50 , 5 to 11 μm; or D 90 , 13 to 50 μm; or a particle size distribution of D 90  equal to or below 50 μm. 
     
     
         9 . The pharmaceutical composition of  claim 1 , comprising 15 to 800 mg of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof. 
     
     
         10 . The pharmaceutical composition of  claim 1 , comprising a pharmaceutically acceptable excipient. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutically acceptable excipient is selected from a filler, a disintegrant, a surfactant, and a lubricant, and combinations thereof, optionally wherein the filler is mannitol and/or microcrystalline cellulose, optionally wherein the disintegrant is croscarmellose sodium, optionally wherein the surfactant is sodium lauryl sulfate, and optionally wherein the lubricant is magnesium stearate. 
     
     
         12 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutically acceptable excipient is selected from a filler, a binder, a disintegrant, a surfactant, a glidant, and a lubricant, and combinations thereof, optionally where in the filler is microcrystalline cellulose, lactose, or mannitol, or a combination thereof, optionally wherein the binder is hydroxypropyl cellulose, optionally wherein the disintegrant is croscarmellose sodium or crospovidone, optionally wherein the surfactant is sodium lauryl sulfate, optionally wherein the glidant is colloidal silicon dioxide, and optionally wherein the lubricant is magnesium stearate. 
     
     
         13 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is a capsule. 
     
     
         14 . The pharmaceutical composition of  claim 13 , wherein the capsule comprises:
 a) 15 to 800 mg of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof;   b) 15% w/w to 75% w/w of a first filler, optionally wherein the first filler is mannitol;   c) 10% w/w to 35% w/w of a second filler, optionally wherein the second filler is microcrystalline cellulose;   d) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium;   e) 0.1% w/w to 1% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate; and   f) 0.1% w/w to 1% w/w of a lubricant, optionally wherein the lubricant is magnesium stearate;   wherein the total % w/w of a) to f) is 100%.   
     
     
         15 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is a tablet. 
     
     
         16 . The pharmaceutical composition of  claim 15 , wherein the tablet comprises:
 a) 35% w/w to 75% w/w of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof;   b) 7% w/w to 40% w/w of a first filler, optionally wherein the first filler is microcrystalline cellulose;   c) 5% w/w to 25% w/w of a second filler, optionally wherein the second filler is lactose anhydrous or mannitol;   d) 2% w/w to 10% w/w of a binder; optionally wherein the binder is hydroxypropyl cellulose;   e) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium or crospovidone;   f) 0.3% w/w to 2% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate;   g) 0.3% w/w to 2% w/w of a lubricant, optionally wherein the lubricant is magnesium stearate; and   h) 0.1% w/w to 1% w/w of a glidant, optionally wherein the glidant is colloidal silicon dioxide;   wherein the total % w/w of a) to h) is 100%.   
     
     
         17 . A pharmaceutical composition comprising about 100 mg to about 500 mg of wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile free base anhydrate. 
     
     
         18 . The pharmaceutical composition of  claim 17 , comprising about 200 mg or about 300 mg of the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile free base anhydrate. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile free base anhydrate has an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. 
     
     
         20 . The pharmaceutical composition of  claim 19 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile free base anhydrate is obtained from a mixture of methyl ethyl ketone (MEK) and isopropanol (IPA). 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile free base anhydrate is obtained from a 1:1 mixture of MEK and IPA. 
     
     
         22 . The pharmaceutical composition of  claim 1 , comprising the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof without other therapeutic agents. 
     
     
         23 . A pharmaceutical composition comprising wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof. 
     
     
         24 . The pharmaceutical composition of  claim 23 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an XRPD pattern with at least three characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. 
     
     
         25 . The pharmaceutical composition of  claim 23 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile Form 1 having an X-ray powder diffraction (XRPD) pattern with at least five characteristic peaks selected from 4.1° 2-Theta, 5.4° 2-Theta, 6.6° 2-Theta, 8.2° 2-Theta, 9.5° 2-Theta, 12.3° 2-Theta, 13.1° 2-Theta, 13.9° 2-Theta, 15.9° 2-Theta, 16.4° 2-Theta, 17.0° 2-Theta, 17.5° 2-Theta, 19.7° 2-Theta, and 22.6° 2-Theta. 
     
     
         26 . The pharmaceutical composition of  claim 23 , wherein the pharmaceutical composition is a capsule comprising:
 a) 15 to 800 mg of wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof;   b) 15% w/w to 75% w/w of a first filler, optionally wherein the first filler is mannitol;   c) 10% w/w to 35% w/w of a second filler, optionally wherein the second filler is microcrystalline cellulose;   d) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium;   e) 0.1% w/w to 1% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate; and   f) 0.1% w/w to 1% w/w of a lubricant, optionally wherein the lubricant is magnesium stearate;   wherein the total % w/w of a) to f) is 100%.   
     
     
         27 . The pharmaceutical composition of  claim 23 , wherein the pharmaceutical composition is a tablet comprising:
 a) 35% w/w to 75% w/w of wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof;   b) 7% w/w to 40% w/w of a first filler, optionally wherein the first filler is microcrystalline cellulose;   c) 5% w/w to 25% w/w of a second filler, optionally wherein the second filler is lactose anhydrous or mannitol;   d) 2% w/w to 10% w/w of a binder; optionally wherein the binder is hydroxypropyl cellulose;   e) 1% w/w to 10% w/w of a disintegrant, optionally wherein the disintegrant is croscarmellose sodium or crospovidone;   f) 0.3% w/w to 2% w/w of a surfactant, optionally wherein the surfactant is sodium lauryl sulfate;   g) 0.3% w/w to 2% w/w of a lubricant, optionally wherein the lubricant is magnesium stearate; and   h) 0.1% w/w to 1% w/w of a glidant, optionally wherein the glidant is colloidal silicon dioxide;   wherein the total % w/w of a) to h) is 100%.   
     
     
         28 . The pharmaceutical composition of  claim 23 , wherein the wet-milled crystalline (S)-4-methyl-5-((4-((2-(methylamino)-6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1-(2-(4-(methylsulfonyl)piperazin-1-yl)propyl)-1H-indole-2-carbonitrile or solvate thereof is obtained from a mixture of methyl ethyl ketone (MEK) and isopropanol (IPA).